Hyperthermia significantly increases chemotherapy induced cytotoxicity for both tumor and normal tissue. Thus, normal tissue injury limits the application of this powerful anti-cancer therapy. in the light of this serious restriction to a potentially effective therapy, there are surprisingly few studies of acute normal tissues reaction to chemotherapy with either local/regional or systemic heat, and no studies of late normal tissue response. The general objective of this continuing research is to establish an optimal thermo-chemotherapy treatment regiment that provides both minimal injury to normal tissue with maximum tumor ablation. The response of a rat fibrosarcoma will be used as a tumor model. We hypothesize that known vascular, metabolic, pH and repair differences between tumors and normal tissues may be exploited to reduce normal tissue damage while maintaining anti-tumor effect. We propose to utilize these dissimilarities between tumor and normal tissues by first establishing dose response curves of local/regional and systemic heat administered simultaneously with the single agents cisplatin, doxorubicin, bleomycin and their respective less toxic analogs. We will first quantitate normal tissue response to the thermochemotherapy; we will then use pharmacokinetic and biochemical pharmacologic studies to optimize drug/heat schedules in order to reduce normal tissue toxicities, retain anti-tumor efficacy of the combined therapy in sensitive tumors and demonstrate activity against resistant tumors. Protective compounds known to reduce specific drug toxicities at normal temperature will then be tested with hyperthermia and drugs to further increase the therapeutic index of the combined modality therapy. Information learned from these studies will be applied to the rational design of a multi-agent chemotherapy-hyperthermia therapy to be used in cancer patients.